Version May 2024
INTRODUCTION — Precocious puberty is the onset of pubertal development at an age that is 2 to 2.5 standard deviations (SD) earlier than population norms. The cause of precocious puberty may range from a variant of normal development (eg, isolated premature adrenarche or isolated premature thelarche) to pathologic conditions with significant risk of morbidity and even death (eg, malignant germ-cell tumor or astrocytoma).
The clinician faced with a child who presents with early development of secondary sexual characteristics should consider the following questions:
●Is the child too young to have reached the pubertal milestone in question? – To answer this question, the clinician needs to know the normal ages for pubertal milestones and how to distinguish normal from abnormal development.
●What is causing the early development? – To answer this question, the clinician ascertains whether the development of secondary sexual characteristics is attributable to androgen and/or estrogen effects and whether the source of sex hormone is centrally mediated through the hypothalamic-pituitary-gonadal axis, from an autonomous peripheral origin, or has an exogenous basis.
●Is therapy indicated, and, if so, what therapy?
The definition of precocious puberty and its causes and evaluation will be reviewed here. The treatment of precocious puberty is discussed separately. (See "Treatment of precocious puberty".)
DEFINITION — Precocious puberty is traditionally defined as the onset of secondary sexual characteristics before the age of eight years in females and nine years in males [1]. These limits are chosen to be 2 to 2.5 standard deviations (SD) below the mean age of onset of puberty. In most populations, attainment of pubertal milestones approximates a normal distribution, with a mean age of onset of puberty of approximately 10.5 years in females and 11.5 years in males (figure 1A-B) and an SD of approximately one year [1-9].
NORMAL PUBERTAL DEVELOPMENT — The hypothalamic-pituitary-gonadal axis is biologically active in utero and briefly during the first week of life. It then becomes more active again during infancy, with peak activity between one and three months of age [10]. This state yields sex steroid levels comparable with those seen in early-to-mid puberty but without peripheral effects. In males, gonadotropin concentrations then decrease to prepubertal levels by six to nine months of age. In females, luteinizing hormone (LH) levels decrease at approximately the same time as in males, but the follicle-stimulating hormone (FSH) concentrations can remain elevated into the second year of life. This hypothalamic-pituitary-gonadal activity during infancy is often referred to as the "mini puberty of infancy"; its biologic relevance is unknown.
The neonatal stage is followed by active suppression of the hypothalamic-pituitary-gonadal axis until puberty occurs. The physiologic and genetic mechanisms that affect timing of pubertal maturation are discussed separately. (See "Normal puberty", section on 'Sequence of pubertal maturation'.)
In 1969 and 1970, Marshall and Tanner defined the stages of normal pubertal development in children and adolescents, known as sexual maturity ratings or "Tanner stages" (picture 1A-C) [2,3]. These studies reported that the first sign of puberty in females was breast development at an average age of 11 years (thelarche), followed by pubic hair growth (pubarche), and then menarche. In males, the first sign was testicular enlargement at an average age of 11.5 years, followed by penile growth and pubic hair growth. (See "Normal puberty".)
Since these reports by Marshall and Tanner, several studies in the United States and other countries suggest that children, especially those with an increased body mass index, enter puberty at a younger age than previously [4,5,7-9,11,12]. These data and the proposed explanations for the trends are discussed separately. (See "Normal puberty", section on 'Trends in pubertal timing'.)
EPIDEMIOLOGY — Using the traditional definition of precocious puberty as the development of secondary sexual characteristics before age eight in females and nine in males (2 to 2.5 standard deviations [SD] below the average age of pubertal onset in healthy children), one would expect that the prevalence rate should be around 2 percent, ie, 2 in every 100 children. However, population studies looking at the prevalence rates of precocious puberty yield markedly different rates depending on the population studied:
●In a population-based study of data from Danish national registries from 1993 to 2001, the incidence of precocious puberty was 20 per 10,000 females and less than 5 per 10,000 males [13]. The diagnostic age limit utilized in this study was eight years for females and nine for males. Approximately one-half the patients had central precocious puberty (CPP), and the remainder were isolated premature thelarche or adrenarche, or early normal pubertal development. (See "Premature adrenarche".)
●In a population-based United States study, breast and/or pubic hair development was present at age eight years in 48 percent of Black females and 15 percent of White females [11]. At seven years of age, the proportions were 27 percent and 7 percent, respectively.
●Another United States study demonstrated a median age of breast development at 8.8 years in Black girls, 9.3 years in Hispanic girls, and 9.7 years in Asian and White non-Hispanic girls [14]. Body mass index accounted for a greater proportion of this variance (14 percent) compared with race/ethnicity (4 percent).
These observations suggest that the definition of precocious puberty is problematic, at least in females, and that selection of children for evaluation should not only depend on age but also on clinical features such as family history and presence/absence of obesity [15].
Although some guidance has suggested that race/ethnicity should be incorporated into decisions about thresholds for the evaluation for precocious puberty [16,17], one has to consider the validity and basis of that approach critically. Associations between genetic ancestry and the timing of puberty have been reported [18], but the correlation is relatively weak, is not observed in all population groups, and decreases with population diversification. Moreover, race/ethnic groups represent social constructs that are often poor surrogates for genetic ancestry. For these reasons, it remains unclear to what degree race/ethnicity is an independent modifier as opposed to a marker for other factors that impact pubertal timing, such as body mass index, exposure to endocrine-disrupting chemicals, and/or other social determinants of health [19]. It is important to incorporate all available clinical information into the decision regarding the evaluation of a child with precocious puberty and not simply attribute earlier pubertal development to racial/ethnic background. (See 'Definition' above and 'Threshold for evaluation' below and "Endocrine-disrupting chemicals", section on 'Precocious puberty'.)
Another consideration is the sex of the child, with a strong female predominance of children evaluated for precocious puberty. In a retrospective review of 104 consecutive children referred for evaluation of precocious puberty, 87 percent were female [20]. Whether this represents a true biologic difference or referral bias is another area of uncertainty.
THRESHOLD FOR EVALUATION — We suggest careful evaluation of children presenting with signs of secondary sexual development younger than the age of eight years in females or nine years in males. The level of concern and extent of evaluation should increase with younger age at presentation but decrease in the presence of factors associated with earlier pubertal timing such as increased adiposity or family history of early pubertal development [11,14]. Neither obesity nor racial/ethnic origin obviates the need for careful assessment [21]. Given the trend towards earlier pubertal development in females who are between the ages of seven and eight, a comprehensive history, physical examination, and careful follow-up may be sufficient if the clinical evaluation does not raise any additional concerns [16]. Routine use of younger age cutoffs is controversial, with concern that they would result in failure to identify some children with true disease [22-24]. The degree and/or rate of pubertal progression should also be taken into account. (See 'Epidemiology' above and 'Evaluation' below and "Normal puberty", section on 'Trends in pubertal timing'.)
CLASSIFICATION — Precocious puberty can be classified based upon the underlying pathologic process (algorithm 1).
●Central precocious puberty (CPP) – CPP (also known as gonadotropin-dependent precocious puberty or true precocious puberty) is caused by early maturation of the hypothalamic-pituitary-gonadal axis. CPP is characterized by sequential maturation of breasts and pubic hair in females and of testicular and penile enlargement and pubic hair in males. In these patients, the pubertal characteristics are appropriate for the child's sex (isosexual). CPP is pathologic in 20 to 75 percent of cases in males [25,26], compared with 10 to 20 percent in females (table 1) [27-29]. (See 'Causes of central precocious puberty' below.)
●Peripheral precocity – Peripheral precocity (also known as peripheral precocious puberty, gonadotropin-independent precocious puberty) is caused by excess secretion of sex hormones (estrogens or androgens) from the gonads or adrenal glands, exogenous sources of sex steroids, or ectopic production of gonadotropin from a germ-cell tumor (eg, human chorionic gonadotropin [hCG]) (table 2). The term precocity is used instead of puberty here because true puberty requires activation of the hypothalamic-pituitary-gonadal axis, as occurs in CPP. Peripheral precocity may be appropriate for the child's sex (isosexual) or inappropriate, with virilization of females and feminization of males (contrasexual). (See 'Causes of peripheral precocity' below.)
●Benign or nonprogressive pubertal variants – Benign clinical pubertal variants include isolated estrogen-mediated breast development in females (premature thelarche) or isolated androgen-mediated sexual characteristics (such as pubic and/or axillary hair, acne, and apocrine odor) in males or females (premature adrenarche, which results from early activation of the hypothalamic-pituitary-adrenal axis, as confirmed by mildly elevated levels of dehydroepiandrosterone sulfate [DHEAS] for age) (table 3). Both of these conditions can be a variant of normal puberty. However, repeat clinical examination, which could be performed by the primary care provider, is warranted to ensure that the diagnosis is correct and there is no rapid and/or expanded pubertal progression (ie, no evidence of both estrogen- and androgen-mediated effects). (See 'Types of benign or nonprogressive pubertal variants' below.)
CAUSES OF CENTRAL PRECOCIOUS PUBERTY — Central precocious puberty (CPP; also known as gonadotropin-dependent precocious puberty) is caused by early maturation of the hypothalamic-pituitary-gonadal axis. Although the onset is early, the pattern and timing of pubertal events is usually normal. These children have accelerated linear growth for age, advanced bone age, and pubertal levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
CPP can be treated with a gonadotropin-releasing hormone (GnRH) agonist, which leads to downregulation of the pituitary response to endogenous GnRH, produces a prepubertal hormonal state, and stops the progression of secondary sexual development, accelerated growth, and undue bone age advancement [17]. (See "Treatment of precocious puberty", section on 'Treatment for central precocious puberty'.)
Idiopathic — CPP is idiopathic in 80 to 90 percent of cases of females but in only 25 to 80 percent of males [25-29]. In some cases, especially those with other affected family members, designation as idiopathic CPP may be due to the presence of genetic variants that are associated with early puberty. (See "Normal puberty", section on 'Physiology and endocrinology of puberty'.)
Central nervous system lesions — Because CPP can be associated with discernible lesions of the central nervous system (CNS), a condition often referred to as neurogenic CPP (table 1), contrast-enhanced magnetic resonance imaging (MRI) is therefore recommended, even in the absence of clinically evident neurologic abnormalities [25,27,29]. However, the low prevalence of CNS lesions in females with the onset of puberty that begins after age six years raises the question if all females in this age group need imaging [28].
Many different types of intracranial disturbances can cause precocious puberty, including the following:
●Hamartomas – Hamartomas of the tuber cinereum are benign tumors that can be associated with gelastic (laughing or crying) and other types of seizures [30]. They are the most frequent type of CNS tumor to cause precocious puberty in very young children, although in most cases, the mechanism by which these tumors lead to CPP is unknown.
●Other CNS tumors – Other CNS tumors associated with precocious puberty include astrocytomas [31], ependymomas, pinealomas, and optic and hypothalamic gliomas [27]. Sexual precocity in patients with neurofibromatosis is usually, but not always, associated with an optic glioma [32]. (See "Clinical manifestations and diagnosis of central nervous system tumors in children".)
●CNS irradiation – Precocious puberty is a rare complication of CNS irradiation, but, when it occurs, it is commonly associated with growth hormone (GH) deficiency [33,34]. In this setting, regardless of height velocity, the GH axis should be evaluated. If testing shows GH deficiency, the patient should be treated with GH combined with GnRH agonist therapy. (See "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood", section on 'Growth hormone deficiency'.)
●Other CNS lesions – Precocious puberty has been associated with hydrocephalus, cysts, trauma, CNS inflammatory disease, and congenital midline defects, such as optic nerve hypoplasia. (See "Congenital and acquired abnormalities of the optic nerve", section on 'Hypoplasia'.)
Genetics — Specific genetic mutations have been associated with CPP, although each appears to be present in only a minority of cases:
●Gain-of-function mutations in the kisspeptin 1 gene (KISS1) [35] and the gene for its G protein-coupled receptor (KISS1R, formerly known as GPR54) [36] have been implicated in the pathogenesis of some cases of CPP, while loss-of-function mutations in KISS1R can cause hypogonadotropic hypogonadism. These observations demonstrate that KISS1/KISS1R is essential for GnRH physiology and for initiation of puberty [37].
●CPP also can be caused by loss-of-function mutations in MKRN3 (the gene encoding makorin ring finger protein 3), an imprinted gene in the Prader-Willi syndrome critical region (15q11-q13). The decline of hypothalamic Mkrn3 expression in mice [38] and serum MKRN3 protein levels in females prior to the onset of puberty [39] indicate that MKRN3 plays an important role in repressing pubertal initiation. Thus, loss-of-function mutations in this gene would lead to diminished inhibition and early onset of puberty. Paternally inherited loss-of-function mutations in MKRN3 have been reported in up to 46 percent of familial cases of CPP and nearly 10 percent of idiopathic cases [38,40-43].
●Loss-of-function mutations in the DLK1 gene (delta-like 1 homolog), leading to undetectable serum concentrations of the DLK1 protein, appear to be rare causes of isolated CPP [44]. Like with MKRN3, affected individuals only develop precocious puberty if the gene mutation is inherited from the father. DLK1 is a paternally expressed gene, mostly in adrenal, pituitary, and ovarian tissue. No definitive mechanistic link between DLK1 function and pubertal development has been determined, but polymorphisms in this gene as well as in MKRN3 are associated with variation in the age of menarche in large genome-wide association studies providing further evidence of a mechanistic link [45].
Pubertal timing is not only modulated by these single-gene disorders but also by common variants in the general population, as have been identified through genome-wide association studies. An emerging area of investigation focuses on the contribution of these common variants to pubertal disorders. Genetic factors involved in pubertal onset are discussed separately. (See "Normal puberty", section on 'Physiology and endocrinology of puberty'.)
Previous excess sex steroid exposure — Children who have been exposed to high serum levels of sex steroid (eg, those with McCune-Albright syndrome and poorly controlled congenital adrenal hyperplasia) may sometimes develop superimposed CPP, either from the priming effect of the peripheral precocity-derived sex steroid on the hypothalamus or in response to the sudden lowering of the sex steroid levels following improved control of the sexual precocity [46-48]. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Monitoring and dose adjustment' and 'McCune-Albright syndrome' below.)
Pituitary gonadotropin-secreting tumors — These tumors are extremely rare in children and are associated with elevated levels of LH and sometimes also FSH [49,50].
CAUSES OF PERIPHERAL PRECOCITY — Peripheral precocity (also known as peripheral precocious puberty or gonadotropin-independent precocious puberty) is caused by excess secretion of sex hormones (estrogens and/or androgens) derived either from the gonads or adrenal glands or from exogenous sources (table 2). Further characterization is based upon whether the pubertal characteristics are appropriate for the child's sex (isosexual) or inappropriate, with virilization of females and feminization of males (contrasexual). Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels are typically suppressed (into the prepubertal range) and do not increase substantially with gonadotropin-releasing hormone (GnRH) stimulation.
The approach to treatment for peripheral precocity depends on the cause. GnRH agonist therapy is ineffective, in contrast to patients with central precocious puberty (CPP). (See "Treatment of precocious puberty", section on 'Treatment for peripheral precocity'.)
In the following discussion, the causes of peripheral precocity are described based upon sex.
Females
Ovarian cysts — A functioning follicular cyst of the ovaries is the most common cause of peripheral precocity in females [51]. Affected patients often present with breast development, followed by an episode of vaginal bleeding, which occurs due to estrogen withdrawal once the cyst has regressed. These cysts may appear and regress spontaneously, so conservative management is usually appropriate [52]. Large cysts may predispose to ovarian torsion.
Ovarian tumors — Ovarian tumors are a rare cause of peripheral precocity in females. Granulosa cell tumors, the most common type, typically present as isosexual precocity; Sertoli/Leydig cell tumors (arrhenoblastoma), pure Leydig cell tumors, and gonadoblastoma may make androgens and cause contrasexual precocity [53-55]. (See "Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults".)
Males
Leydig cell tumors — Leydig cell tumors should be considered in any males with asymmetric testicular enlargement. Even if a distinct mass cannot be palpated and none is evident on ultrasonography, the larger testis should be biopsied if it enlarges during follow-up. These testosterone-secreting tumors are almost always benign and are readily cured by surgical removal [56]. Radical orchiectomy is the most common procedure; however, successful treatment by direct enucleation of the tumor with sparing of the remainder of the testis has been reported [57]. (See "Testicular sex cord stromal tumors", section on 'Leydig cell tumors'.)
Human chorionic gonadotropin-secreting germ-cell tumors — Germ-cell tumors secrete human chorionic gonadotropin (hCG), which, in males, activates LH receptors on the Leydig cells, resulting in increased testosterone production [58]. The increase in testicular size (usually only to an early pubertal size) is less than expected for the serum testosterone concentration and degree of pubertal development. This discrepancy is because most of the testis is made up of seminiferous tubular elements whose maturation depends upon FSH. In females, hCG-secreting tumors do not lead to precocious puberty, because activation of both FSH and LH receptors is needed for estrogen biosynthesis.
These tumors occur in the gonads, brain (usually in the pineal region), liver, retroperitoneum, and anterior mediastinum, reflecting sites of embryonic germ cells before their coalescence in the gonadal ridge [58]. The histology of hCG-secreting tumors ranges from dysgerminoma, which respond readily to therapy, to the more malignant embryonal cell carcinoma and choriocarcinoma. All males with anterior mediastinal germinomas should have a karyotype because these tumors may be associated with Klinefelter syndrome. (See "Clinical manifestations, diagnosis, and staging of testicular germ cell tumors" and "Pathology of mediastinal tumors", section on 'Germ cell tumors'.)
Familial male-limited precocious puberty — This rare disorder (also known as testotoxicosis) is caused by an activating mutation in the LH receptor gene, which results in premature Leydig cell maturation and testosterone secretion [59]. Although inherited as an autosomal dominant disorder, females are not affected clinically, because (similar to hCG-secreting germ tumors) activation of both the LH and FSH receptors is required for estrogen biosynthesis [60]. Also similar to hCG-secreting tumors, the increase in testicular size is usually only to an early pubertal size. Affected males typically present between one to four years of age.
Treatment of this disorder is discussed separately. (See "Treatment of precocious puberty", section on 'Familial male-limited precocious puberty'.)
Both females and males — The following causes of peripheral precocity can occur in either females or males. Physical changes either may be isosexual or contrasexual depending on the sex of the child and the type of sex hormone produced. Excess estrogen will cause feminization, while excess androgen will result in virilization.
Primary hypothyroidism — Children with severe, long-standing primary hypothyroidism occasionally present with precocious puberty. In females, findings include early breast development, galactorrhea, and recurrent vaginal bleeding, while affected males present with premature testicular enlargement [61-63]. Historically, this has been referred to as the "overlap" or Van Wyk-Grumbach syndrome [64]. The signs of pubertal development regress with thyroxine therapy. (See "Acquired hypothyroidism in childhood and adolescence".)
A proposed mechanism is cross-reactivity and stimulation of the FSH receptor by high serum thyrotropin (thyroid-stimulating hormone [TSH]) concentrations, given that both TSH and FSH share a common alpha subunit [65].
Exogenous sex steroids and endocrine-disrupting chemicals — Feminization, including gynecomastia in males, has been attributed to excess estrogen exposure from creams, ointments, and sprays. Caretakers using these topical estrogens to treat menopausal symptoms, for example, may inadvertently expose children to the hormones [66,67]. Other possible sources of estrogen exposure include contamination of food with hormones, phytoestrogens (eg, in soy), and over-the-counter remedies such as lavender oil and tea tree oil [68,69]. Similarly, virilization of young children has been described following inadvertent exposure to androgen-containing creams [70,71]. A food source was suspected for local "epidemics" of early thelarche in Italy and Puerto Rico during the 1980s, but no single causative substance was found in food samples [72-74]. There is ongoing research assessing the influence of endocrine-disrupting chemicals on population trends of earlier onset of puberty as well as their potential role as causative agents of precocious puberty. (See "Endocrine-disrupting chemicals", section on 'Children'.)
Adrenal pathology — Adrenal causes of excess androgen production include androgen-secreting tumors and enzymatic defects in adrenal steroid biosynthesis (congenital adrenal hyperplasia). Males who have an adrenal cause for their precocity will not have testicular enlargement (testes will be <4 mL testicular volume or <2.5 cm in diameter). (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)
Premature pubarche is often caused by premature adrenarche but may also be the presenting feature of an inherited disorder of adrenal steroid metabolism, including 21-hydroxylase deficiency, 11-beta-hydroxylase deficiency, 3-beta-hydroxysteroid dehydrogenase type 2 deficiency, hexose-6-phosphate dehydrogenase deficiency, and phosphoadenosine phosphosulfate synthase type 2 deficiency. (See "Uncommon congenital adrenal hyperplasias".)
Adrenal estrogen-secreting tumors can lead to feminization. Rarely, adrenal tumors may produce androgen and estrogen, the latter because of intra-adrenal aromatization of androgen (or production of enough androgen that is peripherally aromatized to estrogen), causing both male and female pubertal changes [75]. (See "Clinical presentation and evaluation of adrenocortical tumors".)
McCune-Albright syndrome — McCune-Albright syndrome (MAS; MIM #174800) is a rare disorder defined as the triad of peripheral precocious puberty, irregular café-au-lait ("coast of Maine") skin pigmentation (picture 2), and fibrous dysplasia of bone (image 1) [76,77]. MAS should be considered in females with recurrent formation of follicular cysts and cyclic menses [78]. The skin manifestations and bone lesions may increase over time. In females presenting with vaginal bleeding, the ovarian enlargement has often been mistaken for an ovarian tumor, leading to unnecessary oophorectomy [79]. Females presenting with premature vaginal bleeding should therefore be evaluated for features of MAS to avoid this potential mistake.
The clinical phenotype varies markedly, depending on which tissues are affected by the mutation, but precocious puberty is the most commonly reported manifestation [80]. As in other forms of peripheral precocity, the sequence of pubertal progression may be abnormal, in that vaginal bleeding often precedes significant breast development [81]. Prolonged exposure to elevated levels of sex steroids may cause accelerated growth, advanced skeletal maturation, and compromised adult height. Although the precocious puberty is typically peripheral precocity, a secondary component of CPP may develop because of sex steroid withdrawal leading to activation of the hypothalamic-pituitary-gonadal axis [82] (see 'Previous excess sex steroid exposure' above). In males with MAS, while sexual precocity is less common, there is a high prevalence of testicular pathology on ultrasound, including hyper- and hypoechoic lesions (most likely representing areas of Leydig cell hyperplasia), microlithiasis, and focal calcifications [83,84].
Patients with MAS have a somatic (postzygotic) mutation of the alpha subunit of GNAS, which encodes the Gs protein that activates adenylyl cyclase [85-87]. This mutation leads to continued stimulation of endocrine function, including precocious puberty, thyrotoxicosis, growth hormone excess (gigantism or acromegaly), Cushing syndrome, and renal phosphate wasting (hypophosphatemic rickets) in various combinations. Mutations can be found in other nonendocrine organs (liver and heart) resulting in cholestasis and/or hepatitis, intestinal polyps, and cardiac arrhythmias, respectively [77]. A heightened risk of malignancy has also been reported [88]. Germline occurrences of this mutation would presumably be lethal [85,87,89,90].
Treatment of precocious puberty associated with MAS is described in a separate topic review (see "Treatment of precocious puberty", section on 'McCune-Albright syndrome'). More detailed information, including evaluation and management of associated skeletal abnormalities, renal phosphate wasting and endocrine abnormalities, is described in a guideline from an international consortium [77].
TYPES OF BENIGN OR NONPROGRESSIVE PUBERTAL VARIANTS — Early pubertal development fits into this category when the early development of secondary sexual characteristics does not herald underlying pathology and is not followed by progressive development (table 3). However, monitoring for evidence of pubertal progression is important as some children presenting with an apparent benign pubertal variant will instead turn out to have a disorder. As examples, thelarche may be the initial presenting feature of central precocious puberty (CPP) or progressive pubic hair development may herald a form of peripheral precocity.
Premature thelarche — Most cases of premature thelarche are idiopathic and present under two years of age (and may even start at birth). Many cases will remit spontaneously, and most others do not progress. However, follow-up is warranted because premature thelarche can represent the initial presentation of true CPP in as many as 10 to 20 percent of children referred to pediatric endocrine units [91-93].
Key features of premature thelarche are:
●Isolated breast development, either unilateral or bilateral – Typically not developing beyond Tanner stage 3
●Absence of other secondary sexual characteristics
●Normal height velocity for age (not accelerated)
●Normal or near-normal bone age
Serum luteinizing hormone (LH) and estradiol concentrations are typically in the prepubertal range, but one should be cautious in interpreting these levels in children under the age of two years because elevations can be seen as part of the normal transient "mini-puberty of infancy," and CPP can be diagnosed inappropriately (See 'Normal pubertal development' above.)
Toddlers and children — Premature thelarche occurs in two peaks: one during the first two years of life and the other at six to eight years of age [93], with potentially different underlying pathophysiology accountable for each of these peaks. Postulated mechanisms include transient activation of the hypothalamic-pituitary-gonadal axis with excess follicle-stimulating hormone (FSH) secretion [94]. In infants, soy-based formulas have been implicated, although the evidence is weak and may represent only a slower waning of breast tissue during infancy [95-97]. Use of lavender oil, tea tree oil, or hair care products that contain placental extract has also been implicated in some cases of premature thelarche [68]. In most instances, no cause can be found.
In most cases, premature thelarche requires only reassurance. However, the patient should be examined for other signs of pubertal development and growth data should be plotted; an accelerated height velocity may be indicative of progressive puberty and requires further evaluation. To identify patients with progressive puberty, patients should be monitored for several months for evidence of pubertal progression. (See 'Evaluation' below.)
Neonates — Breast hypertrophy can occur in neonates of both sexes and is sometimes quite prominent. It is caused by stimulation from maternal hormones and usually resolves spontaneously within a few weeks or months. The breast development may also be associated with galactorrhea ("witch's milk"), which also resolves spontaneously [98]. While in most cases, neonatal thelarche disappears over the first months of life, failure to do so almost never has any pathologic significance. (See "Breast masses in children and adolescents", section on 'Neonates and infants'.)
Premature adrenarche — Premature adrenarche is characterized by the appearance of pubic and/or axillary hair, apocrine odor, and/or acne (pubarche) prior to the age of eight years in females and nine years in males, in conjunction with a mild elevation in serum dehydroepiandrosterone sulfate (DHEAS) for age. Premature adrenarche is more common in children who are female, born small for gestational age, Black or Hispanic (at least in the United States), and/or have obesity and insulin resistance [16]. Premature adrenarche is considered a variant of normal development but may be a risk factor for later development of polycystic ovary syndrome in females. (See "Premature adrenarche" and "Definition, clinical features, and differential diagnosis of polycystic ovary syndrome in adolescents".)
In the child presenting with pubic hair alone (isolated pubarche) and other features of premature adrenarche, monitoring for the development of other secondary sexual characteristics (breast or testicular enlargement) is important to ensure that the child's presentation is not the first feature of CPP or a form of peripheral precocity. Premature adrenarche can be associated with mild growth acceleration and advance in bone age. In children with progressive virilization or with a more advanced bone age (>2 standard deviations [SD] beyond chronologic age), further investigation for other causes of early pubertal development should be considered. (See "Premature adrenarche", section on 'Initial evaluation of premature pubarche'.)
Pubic hair of infancy — Pubic hair of infancy is usually a benign condition where infants present with isolated genital hair, usually finer in texture than typical pubic hair and located along the labia or over the scrotum (rather than on the pubic symphysis) [99-101]. The steroid profile of these infants demonstrates normal or mildly elevated DHEAS concentrations for age. Unlike premature adrenarche, the condition is transient and the hair typically disappears within 6 to 24 months [102]. In the absence of progressive development of further genital hair or other secondary sexual characteristics during follow-up, extensive evaluation is not needed.
Benign prepubertal vaginal bleeding — Benign prepubertal vaginal bleeding is characterized by the presence of isolated, self-limited vaginal bleeding in the absence of other secondary sexual characteristics [103]. The underlying etiology is unknown, but potential mechanisms include increased endometrial sensitivity to circulating estrogens or transient stimulation of the hypothalamic-pituitary-gonadal axis [104]. Pelvic ultrasonography is normal, and gonadotropins are prepubertal. Genital or vaginal trauma, infection, and sexual abuse should be excluded. In girls with recurrent episodes of vaginal bleeding, other diagnoses, such as recurrent functional ovarian cysts or McCune-Albright syndrome, should be considered. These conditions may not be initially recognized, because vaginal bleeding is associated with regression of the ovarian cyst and, hence, an ultrasound conducted at or after bleeding has occurred may be normal. (See 'McCune-Albright syndrome' above.)
Nonprogressive or intermittently progressive precocious puberty — A subgroup of patients presenting with what clinically appears to be CPP (often with evidence of both gonadarche and pubarche) will either have stabilization or very slow progression in their pubertal signs [105]. The bone age is typically not as advanced compared with children with true CPP, and serum LH concentrations are within the pre- or early-pubertal range, indicating that the hypothalamic-pituitary-gonadal axis is not fully activated and a FSH-predominant response is typically seen if gonadotropin-releasing hormone (GnRH) agonist stimulation testing is performed. Monitoring for evidence of pubertal progression is important to distinguish these children from those with true CPP. In children with nonprogressive precocious puberty, treatment with a GnRH agonist is not needed, because their adult height is not affected (ie, their adult height untreated is concordant with their midparental height) [105,106].
EVALUATION
Guiding principles — The evaluation for precocious puberty focuses on answering the following questions:
●Who should be evaluated? – Evaluation is warranted in children presenting with signs of secondary sexual development younger than the age of eight (females) or nine (males) years. The concern and extent of evaluation should increase with decreasing age at presentation and increasing degree and/or rate of pubertal progression, as outlined below. In females who are between the ages of seven and eight, a comprehensive history and physical examination may be sufficient if this examination does not raise any additional concerns.
●Is the cause of precocity central or peripheral? – The sequence of pubertal development in children with central precocious puberty (CPP) recapitulates normal pubertal development but at an earlier age (figure 1A-B). By contrast, individuals with peripheral precocity have a peripheral source of gonadal hormones and are more likely to display deviations from the normal sequence and/or pace of puberty. As an example, a female who progresses to menstrual bleeding within one year of the onset of breast development is more likely to have ovarian pathology (a cause of peripheral precocity) rather than CPP [107,108].
●How quickly is the puberty progressing? – The pace of pubertal development reflects the degree and duration of sex steroid action.
•A rapid rate of linear growth and skeletal maturation (measured as advanced bone age) suggests either peripheral precocity or CPP, with concern raised for a neurogenic cause of CPP if the tempo is abnormally fast (table 4). Pubertal progression would be considered slow if there is minimal or no change in the stage of breast, pubic hair, or genital development during six or more months of observation. Height velocity is considered accelerated if it is more than the 95th percentile for age (figure 2A-B).
•By contrast, a child with normal linear growth and skeletal maturation (bone age normal or minimally advanced) suggests a benign pubertal variant with low concentrations of sex steroids, rather than true CPP or peripheral precocity.
●Is the precocity because of excess androgen or estrogen? – Are the secondary sexual characteristics virilizing or feminizing? Isolated contrasexual development (isolated virilization in females or isolated feminization in males) excludes central etiologies. While in females the most common cause of virilization is due to excess adrenal androgens, a rare ovarian cause of virilization is ovarian arrhenoblastoma (Sertoli-Leydig cell tumor) [109]. Conversely, a rare testicular cause of feminization is a feminizing Sertoli cell tumor, which may be associated with Peutz-Jeghers syndrome [110]. (See "Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults" and "Testicular sex cord stromal tumors", section on 'Sertoli cell tumors'.)
Initial evaluation — The evaluation of a patient suspected to have precocious puberty begins with a history and physical examination. In most cases, radiographic measurement of bone age is performed to determine whether there is a corresponding increase in epiphyseal maturation.
●Medical history – The history focuses on when the initial pubertal changes were first noted, as well as the timing of pubertal onset in the parents and siblings. In addition, other questions are directed toward evidence of linear growth acceleration, headaches, changes in behavior or vision, seizures, or abdominal pain (indicative of either a central nervous system [CNS] or ovarian process) and previous history of CNS disease or trauma. The possibility of exposure to exogenous sex steroids (medicinal or cosmetic sources) or compounds with sex steroid-like properties (endocrine-disrupting chemicals, for example) should always be explored [66].
●Physical examination – This includes height, weight, and height velocity (cm/year). Children with benign forms of precocious puberty do not usually display the early growth acceleration pattern that is seen among those with progressive forms of precocious puberty [111]. The physical examination should include assessment of visual fields (a defect suggests the possibility of a CNS mass) and examination for café-au-lait spots (which would suggest neurofibromatosis or McCune-Albright syndrome) (picture 2). (See 'McCune-Albright syndrome' above.)
●Pubertal staging – Secondary sexual development should be assessed to determine the sexual maturity rating (Tanner stage) of pubertal development. This means staging breast development in females (picture 1A), genital development in males, and pubic hair development in both sexes (picture 1B-C). In females, the diameter of glandular breast tissue (by direct palpation including compression to differentiate from adipose tissue when warranted) and the nipple-areolar complex should be assessed. In males, measurements are made of the testicular volume (figure 3) [112]. Penile size (stretched length of the non-erect penis, measuring from the pubic bone to tip of glans, excluding the foreskin) is rarely used for monitoring of pubertal progress because penile growth is not an early event in puberty, accurate measurement is difficult and may be awkward for the adolescent boy, and the "pubertal threshold" for penile-stretched length is not as clear as it is for testicular volume. Accurate measurements of testicular volume are critical to determine whether further radiologic or laboratory testing is necessary. (See "Normal puberty", section on 'Sexual maturity rating (Tanner stages)' and "Normal puberty", section on 'Sequence of pubertal maturation'.)
●Bone age – In patients with advanced or progressive development of secondary sexual characteristics confirmed by physical examination, evaluation of skeletal maturation by radiographic assessment of bone age should be performed. The bone age can help with both the differential diagnosis and assessment of whether there may be an impact on adult height. However, in patients presenting with typical features indicative of either isolated premature thelarche or adrenarche, a bone age may not be necessary, as initial close clinical observation for pubertal progression is likely sufficient.
A significant advance in the bone age (greater than approximately 2 standard deviations [SD] beyond chronologic age) is more likely to be indicative of either CPP or peripheral precocity rather than a benign pubertal variant. A significantly advanced bone age does not, however, exclude a diagnosis of a benign pubertal variant. As an example, up to 30 percent of children with benign premature adrenarche have bone ages more than two years in advance of their chronologic age [113]. (See 'Types of benign or nonprogressive pubertal variants' above.)
Initial laboratory evaluation — If there is evidence of progressive development of secondary sexual characteristics, further evaluation is needed to determine its cause, whether therapy is needed, and, if so, which treatment is appropriate.
The first step is to measure basal luteinizing hormone (LH), follicle-stimulating hormone (FSH), and either estradiol and/or testosterone concentrations. The results are used to differentiate between CPP and peripheral precocity, which then guides additional testing (algorithm 1 and table 4).
Basal serum luteinizing hormone — A good initial screening test to identify activation of the hypothalamic-pituitary-gonadal axis is measurement of basal LH concentration (ideally in the morning), using sensitive immunochemiluminescence assays with a lower limit of detection of ≤0.1 mIU/mL (where mIU = milli-international units) [114]. Results are interpreted as follows:
●LH concentrations in the prepubertal range (ie, <0.2 mIU/mL) are consistent with either peripheral precocity or a benign pubertal variant such as premature thelarche.
●LH concentrations greater than 0.2 to 0.3 mIU/mL (the threshold depends on the assay used) can identify children with progressive CPP with high sensitivity and specificity [17,115-117].
●LH concentrations are less informative in the evaluation of children with nonprogressive or intermittently progressive precocious puberty. While such children typically have basal LH concentrations <0.2 to 0.3 mIU/mL, levels can be in the early pubertal range in some children. Additional clinical characteristics such as lack of progression in secondary sexual characteristics or low LH:FSH ratio post-gonadotropin stimulation test can help to differentiate these children from those with progressive CPP. (See 'Serum LH concentrations after GnRH agonist stimulation' below.)
Care should be used in the interpretation of LH levels in females under the age of two years as gonadotropin concentrations may be elevated at this age in association with the "mini-puberty of infancy" and CPP can be misdiagnosed during this phase of development [10,118].
Basal serum follicle-stimulating hormone — Basal FSH concentrations have limited diagnostic utility in distinguishing children with CPP from those with benign pubertal variants. FSH concentrations are often higher in children with CPP compared with benign pubertal variants, but there is substantial overlap between these groups of children [114,115]. Like LH, FSH concentrations are typically suppressed in children with peripheral precocity.
Serum estradiol — High concentrations of estradiol, with associated suppression of gonadotropins, are generally indicative of peripheral precocity, such as from an ovarian tumor or cyst. Most estradiol immunoassays, however, have poor ability to discriminate at the lower limits of the assay between prepubertal and early pubertal concentrations [119]. More sensitive methods of estimating estradiol concentrations, such as tandem mass spectrometry, distinguish better between prepubertal and pubertal estradiol concentrations [120] and should be ordered exclusively. However, further studies are still needed to clarify threshold concentrations.
Serum testosterone — Testosterone levels are ideally measured between 8 and 10 AM as normative data are based on samples obtained during this time window and low levels at other times of day may be misleading. Elevated testosterone concentrations are indicative of testicular testosterone production in males, or of adrenal testosterone production or exogenous exposure in both sexes. High concentrations, with associated suppression of gonadotropins, are generally indicative of peripheral precocity. Measurement of other adrenal steroids (eg, dehydroepiandrosterone sulfate [DHEAS]) may be necessary to help discriminate between adrenal and testicular sources of the androgens.
In children with CPP, testosterone immunoassays cannot always distinguish between prepubertal and early pubertal testosterone concentrations, but tandem mass spectroscopy methods are more discriminative [121] (similar to the estradiol assays discussed above), so these should be ordered whenever available.
Emerging approaches — Emerging approaches to identify cases of progressive CPP include first-morning urinary gonadotropin levels and serum inhibin B and irisin levels [122-126]. These early results need further validation but could be an important alternative diagnostic strategy in the future.
Subsequent laboratory testing — Subsequent laboratory testing depends on the results of the tests outlined above (basal LH, FSH, and estrogen or testosterone) and on the patient's clinical characteristics:
Serum LH concentrations after GnRH agonist stimulation — In children in whom the clinical picture is discordant with the initial baseline investigations (ie, ongoing pubertal progression with a basal LH in the prepubertal range [ie, <0.2 mIU/mL] (see 'Basal serum luteinizing hormone' above)), a gonadotropin-releasing hormone (GnRH) stimulation test may help differentiate those with CPP from those with a benign pubertal variant. This test consists of measurement of serum LH concentrations before and after administration of GnRH. A GnRH agonist may be used instead of GnRH because a single dose of a GnRH agonist has an initial stimulatory effect on the hypothalamic-pituitary-gonadal axis; this alternative is especially convenient when GnRH is not available (as is the case in the United States).
A common protocol is as follows:
●Blood is sampled at baseline for LH, FSH, and either estradiol in females or testosterone in males.
●The child is then given a single dose of GnRH at a dose of 100 mcg or the GnRH agonist leuprolide acetate at a dose of 20 mcg/kg.
●LH is measured at 30 to 40 minutes post-GnRH or 60 minutes post-GnRH agonist [127-129]. Other protocols employ sampling every 30 minutes for up to two hours [127,130] or testing of estradiol or testosterone 24 hours later [131,132].
The results are interpreted as follows:
●Peak stimulated LH – The optimal cutoff value of peak stimulated LH for identifying children with CPP has not been established and varies somewhat among assays. For most LH assays, a value of 3.3 to 5 mIU/mL defines the upper limit of normal for stimulated LH values in prepubertal children [127,133]. Stimulated LH concentrations above this normal range suggest CPP.
●Peak stimulated LH:FSH ratio – Children with progressive CPP tend to have a more prominent LH increase post-stimulation and higher peak LH:FSH ratios compared with those with non- or intermittently progressive precocious puberty [131,134]. While a definite diagnostic threshold has not been well defined, a peak LH:FSH ratio >0.66 is typically seen with CPP, whereas a ratio <0.66 suggests nonprogressive precocious puberty [134].
●Stimulated estradiol/testosterone – Children with progressive CPP tend to have higher stimulated serum estradiol and testosterone concentrations when measured 24 hours after administration of GnRH or GnRH agonist [131,132]. However, the disadvantage of requiring venipunctures on two consecutive days as well as the lack of consistent published diagnostic thresholds limits the clinical utility of these measurements.
As with basal LH levels, care must be taken in interpreting the results of GnRH stimulation test in females under the age of two years, as both basal and stimulated LH levels can be elevated as part of the normal hormonal changes associated with the mini-puberty of infancy [118].
Serum adrenal steroids — In children with precocious pubarche, measurement of adrenal steroids may be necessary to help distinguish between peripheral precocity and benign premature adrenarche. Children with premature adrenarche can have mild elevation in adrenal hormones, with DHEAS concentrations of 40 to 135 mcg/dL (1.1 to 3.7 micromol/L), and testosterone levels ≤35 ng/dL (1.2 nmol/L) [135]. (See "Premature adrenarche", section on 'Laboratory tests'.)
Concentrations above these thresholds warrant further investigation for causes of peripheral precocity, such as nonclassic congenital adrenal hyperplasia and virilizing adrenal tumors. An early-morning 17-hydroxyprogesterone (17-OHP) value >200 ng/dL (6 nmol/L) has a high sensitivity and specificity for nonclassic congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency [136-138], although an adrenocorticotropic hormone (ACTH) stimulation test is still needed to confirm the diagnosis. A 17-OHP >1500 ng/dL (45 nmol/L) is essentially diagnostic for nonclassic congenital adrenal hyperplasia. In contrast, a mildly elevated 17-OHP between 115 and 200 ng/dL (4.1 to 6.0 nmol) is more consistent with a diagnosis of benign premature adrenarche. (See "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Premature adrenarche".)
Other biochemical tests — Human chorionic gonadotropin (hCG) can be measured in males to evaluate for the possibility of an hCG-secreting tumor leading to peripheral precocity. If a tumor is found in the anterior mediastinum, a karyotype should be performed to evaluate for Klinefelter syndrome because of its association with mediastinal germinoma [58]. A thyroid-stimulating hormone (TSH) concentration should be measured if chronic primary hypothyroidism is suspected as the underlying cause for the sexual precocity.
Imaging
Children with central precocious puberty
●Brain MRI – Indications for performing a contrast-enhanced brain MRI depend on patient characteristics, which predict the risk of CNS abnormalities (see 'Central nervous system lesions' above):
•Males – For all males with CPP (ie, onset <9 years), perform MRI because of relatively high rates of CNS abnormalities.
•Females – For females with CPP, our approach to imaging depends on the age of onset:
-Onset <6 years – Perform MRI because of relatively high rates of CNS abnormalities in this age group.
-Onset between six and seven years – Whether to routinely perform MRI for this group is less clear because data are conflicting about the risk for CNS pathology. In a 2018 meta-analysis, the prevalence of intracranial lesions was 3 percent among females presenting with CPP after six years of age, compared with 25 percent among those presenting before six years [139]. In contrast, some studies not included in this meta-analysis have reported higher rates of MRI brain abnormalities for females with CPP onset after six years of age, with one report of abnormalities in as many as 59 percent of subjects, although only 10 percent had brain tumor or tumor-like lesions [27,140]. Because there are not clear methodologic or population-based reasons for the disparities in reported rates of pathology, recommendations around imaging in this age group remain controversial. A younger age of onset of pubertal signs and higher basal LH and estradiol concentrations have been proposed as predictive features for intracranial pathology [27,28,141]. Still, because these features and clinical suspicion have been shown to have variable sensitivity to detect females with abnormal brain MRIs, some have recommended imaging for all females with CPP regardless of age of onset [27,29,140,142].
-Onset between seven and eight years – Our usual practice is to not perform MRI for those with normal tempo and sequence of pubertal development and no clinical evidence of CNS pathology, especially if there is a family history of earlier pubertal onset.
●Pelvic ultrasound – Pelvic ultrasonography may be a useful adjunct investigation to help differentiate between CPP and benign pubertal variants, especially when the evaluation remains equivocal. Females with CPP have greater uterine and ovarian volumes compared with females who are prepubertal or those with premature thelarche [143-146]. Diagnostic thresholds for uterine and ovarian volumes have been proposed; however, these are variable and some studies have suggested that there is considerable overlap between patients with and without CPP [143,144].
Children with peripheral precocity
●In females with progressive peripheral precocity, a pelvic ultrasound should be performed to help identify the presence of an ovarian cyst or tumor. As noted above, the presence of a normal ovarian ultrasound does not exclude a diagnosis of a functional ovarian cyst, because the cyst may have regressed by the time of the study. (See 'Benign prepubertal vaginal bleeding' above.)
●Ultrasound examination of the testes, especially if asymmetric in size, should be performed in males with peripheral precocity to evaluate for the possibility of a Leydig cell tumor.
●In females and males, peripheral precocity and progressive virilization and/or markedly elevated serum adrenal androgens (eg, DHEAS) occasionally are caused by an adrenal tumor. If other diagnoses such as congenital adrenal hyperplasia and exogenous androgen or testosterone exposure have been excluded, such patients should have an ultrasound or computed tomography (CT) of the adrenal glands.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Normal puberty and puberty-related disorders".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Early puberty (The Basics)")
SUMMARY
●Definition – Precocious puberty is defined as the onset of pubertal development more than 2 to 2.5 standard deviations (SD) earlier than the average age (figure 1A-B). (See 'Definition' above.)
●Threshold for evaluation – Because of the trend of earlier pubertal development, there is controversy about the lower age limit for normal pubertal development. Nonetheless, we recommend evaluation in children presenting with secondary sexual development younger than eight years in females or nine years in males (figure 4). Decisions regarding the evaluation of a child with precocious puberty should incorporate all available clinical information; earlier pubertal development should not be simply attributed to a young person's weight status or racial/ethnic background. (See 'Definition' above and 'Evaluation' above.)
●Classification – The etiology of precocious puberty is classified by the underlying pathogenesis into three categories (see 'Classification' above):
•Central precocious puberty (CPP) is caused by an early activation of the hypothalamic-pituitary-gonadal axis. CPP is idiopathic in 80 to 90 percent of females and 25 to 80 percent of males; the remainder have pathologic causes (eg, brain tumor) (table 1). (See 'Causes of central precocious puberty' above.)
•Peripheral precocity is caused by gonadotropin hormone-independent secretion of sex hormones from the gonads, abnormal production of sex hormones by the adrenal glands, ectopic human chorionic gonadotropin (hCG) production by a germ-cell tumor, or exogenous sources of sex steroids (table 2). (See 'Causes of peripheral precocity' above.)
•Benign pubertal variants include isolated breast development (premature thelarche), isolated pubic hair development (premature pubarche/adrenarche), benign prepubertal vaginal bleeding, and nonprogressive precocious puberty (table 3). These patterns are usually a variant of normal puberty; patients should be followed clinically for signs of progression. (See 'Types of benign or nonprogressive pubertal variants' above.)
●Initial evaluation – The first step is a focused history and physical examination with pubertal staging. If this evaluation confirms advanced or progressive development of secondary sexual characteristics, perform a radiographic assessment of bone age. Advanced bone age suggests precocious puberty rather than a benign pubertal variant but is not definitive. (See 'Initial evaluation' above.)
●Laboratory testing – For children with advanced or progressive development of secondary sexual characteristics on examination, the next step is to measure basal (unstimulated) luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol and/or testosterone concentrations. Results can differentiate between CPP and peripheral precocity, which then guide additional testing (algorithm 1 and table 4).
•Elevated LH (greater than or equal to 0.2 to 0.3 mIU/mL, depending on the assay) suggests CPP. By contrast, LH concentrations in the prepubertal range (ie, <0.2 mIU/mL) are consistent with either peripheral precocity or a benign pubertal variant. (See 'Basal serum luteinizing hormone' above.)
•FSH has limited diagnostic utility in identifying children with CPP but is typically suppressed in children with peripheral precocity. The utility of estradiol and testosterone concentrations in diagnosing CPP is dependent on the measurement method used. (See 'Initial laboratory evaluation' above.)
●Further evaluation for selected patients
•Gonadotropin-releasing hormone (GnRH) stimulation test – If the clinical picture is discordant with the initial baseline investigations (ie, ongoing pubertal progression with a prepubertal basal LH level <0.2 mIU/mL), a GnRH stimulation test can be performed to help distinguish CPP from a benign pubertal variant. Children with CPP have a pubertal (heightened) LH response to GnRH stimulation (table 4). (See 'Serum LH concentrations after GnRH agonist stimulation' above.)
•Imaging – Recommendations for imaging depend on the type of precocious puberty (see 'Imaging' above):
-CPP – All males with CPP should have brain MRI because of the high prevalence of central nervous system (CNS) lesions in this group (table 1). Brain MRI should also be performed in all females with onset of CPP before six years of age; there is ongoing controversy about the need for routine imaging of females with CPP onset between six and eight years of age. (See 'Children with central precocious puberty' above.)
-Peripheral precocity – Males with peripheral precocity may warrant an ultrasound examination of the testes to evaluate for the possibility of a Leydig cell tumor (table 2). Females with peripheral precocity may warrant a pelvic ultrasound performed to help identify the presence of an ovarian cyst or tumor. (See 'Children with peripheral precocity' above.)
In females and males, peripheral precocity and progressive virilization and/or markedly elevated serum adrenal androgens (eg, dehydroepiandrosterone sulfate [DHEAS]) occasionally is caused by an adrenal tumor (table 2). If other diagnoses such as congenital adrenal hyperplasia and exogenous androgen or testosterone exposure have been excluded, such patients should have an ultrasound or CT of the adrenal glands.
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Paul Saenger, MD, MACE, who contributed to earlier versions of this topic review.
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